Tuberculosis kills nearly 2 million people globally every year. While macrophages represent one of our primary defense mechanisms against Mycobacterium tuberculosis (Mtb) infections, Mtb is rarely sterilized from the host. Over the years, we have determined that the Mtb proteasome is essential to allow the tubercle bacilli to persist in vivo. Proteasomes are multi-subunit, barrel shaped proteases that degrade proteins in a highly regulated manner. While we have discovered several pathways linking degradation to virulence, others still remain to be identified. We are currently examining how regulated proteolysis contributes to nitrogen metabolism, which may represent a major role for the proteasome during infections. In addition, we discovered the proteasome regulates the production of cytokinins, a family of signaling molecules that had only been characterized in plants. We further found cytokinins induce transcriptional changes in Mtb, the mechanisms of which will likely represent a new paradigm in bacterial signal transduction and physiology.